Insulin resistance is a key component in the pathogenesis of type 2 diabetes mellitus (DM), and is present early in the disease process. Individuals with a family history of type 2 DM are at high risk for later development of the disorder, and skeletal muscle insulin resistance in these individuals can be observed several years prior to the onset of abnormal glucose tolerance. Weight loss improves the insulin resistance of skeletal muscle, and weight loss is a cornerstone of type 2 DM therapy. Moreover, recent evidence suggests that weight loss may play a role in the prevention of type 2 DM. An enhanced understanding of the pathogenesis of insulin resistance in this disorder; and the potential for weight loss to reduce insulin resistance, could advance efforts in the prevention and treatment of this disorder. This award will provide an opportunity for the candidate, Katherine Williams M.D., M.P.H., to learn specific skills necessary to develop into an independent clinical investigator with the overall goal of linking interventional studies with state-of-the-art physiological assessments of substrate metabolism. As a fellow in Endocrinology and Metabolism, she studied lifestyle interventions for weight loss in patients with type 2 DM and their impact upon glucose metabolism, particularly insulin resistance within skeletal muscle, under the primary mentorship of David Kelley, M.D. Glucose transport into skeletal muscle is regarded as the rate-limiting step in insulin resistance., but it has been methodologically difficult to assess the transport step during clinical investigations of glucose metabolism, Dr, Kelley's laboratory has used PET imaging of [F-18]- labeled fluorodeoxyglucose (FDG) uptake into muscle, during insulin- stimulated conditions, to quantify the severity of skeletal muscle insulin resistance and to measure rate constants for glucose transport and phosphorylation. Based on the physiologic modeling of dynamic patterns of tissue activity of FDG, impairments in the rate constants for glucose transport have been found in obese subjects, and defects in both glucose transport and phosphorylation have been found in obese subjects with type 2 DM. Using this technique, Dr. Williams will test the hypothesis that defects of glucose transport and glucose phosphorylation are present in the obese offspring of parents with type 2 DM. Using her prior training in conducting weight loss interventions, she will further test the hypothesis that weight-loss improves glucose transport and phosphorylation in 3 groups of obese subjects: 1) subjects with no family history and type 2 DM and normal glucose tolerance, 2) subjects with a parental history of type 2 DM and normal glucose tolerance, and 3) subjects with type 2 DM.